NAMI-A, imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, is a
ruthenium-based drug characterised by the selective activity against tumour
metastases. Previously we have shown the influence of the hepatic microenvironment to direct the arrest of the metastatic cells of
colorectal cancer. Here we used the experimental model of HCT-116
colorectal cancer cells in vitro to explore whether the interference with α5β1
integrin may mechanistically explain the anti-metastatic effect of
NAMI-A.
NAMI-A inhibits two important steps of the tumour metastatic progression of
colorectal cancer, i.e. the adhesion and migration of the tumour cells on the
extracellular matrix proteins. The
fibronectin receptor α5β1
integrin is likely involved in the anti-adhesive effects of
NAMI-A on the HCT-116
colorectal cancer cells during their interaction with the extracellular matrix. Mechanistically,
NAMI-A decreases the α5β1
integrin expression, and reduces FAK (
Focal Adhesion Kinase) auto-phosphorylation on Tyr397, an important signalling event, involved in α5β1
integrin activation. These effects were validated by
siRNA-induced knock down of the α5
integrin subunit and/or by the use of specific blocking mAbs against the active site of the
integrin. Our results demonstrate the relevance of α5β1
integrin for
colorectal cancer. We also show that the anti-metastatic effect of
NAMI-A depends on the modulation of this
integrin. Thus, our data on
NAMI-A support the new concept that
metal-based drugs can inhibit tumour
metastases through targeting of
integrins and of other
proteins which mediate tumour progression-related cell functions such as adhesion and migration.